Targeted Next-Generation Sequencing Reveals Heterogenous Genomic Features in Viscerally-Metastatic Prostate Cancer.

BACKGROUND To explore the genomic features of bone-only metastasis (bmPCa), hepatic metastasis (hmPCa) and pulmonary metastasis without liver involvement (pmPCa) in prostate cancer (PCa) using targeted next-generation sequencing. METHODS A hybridization capture-based next-generation sequencing was performed to detected genomic alterations in 50 genes, including androgen receptor (AR), DNA damage response (DDR) and other clinical relevant drivers. RESULTS We successfully sequenced ctDNA from 109 blood samples and 29 metastatic tissue samples from 129 metastatic castration-resistant PCa(mCRPC). We observed distinct genomic profiles of mCRPC across various metastatic sites. High prevalence of PTEN alteration was found in viscerally-metastatic PCa compared with bmPCa(PTEN, 9.09% vs. 2.08%, p=0.105). When comparing viscerally-metastatic PCa according to the metastatic sites, AR alteration rarely occurs in pmPCa, which stood in great contrast to the high alteration frequency in hmPCa (0.0% vs. 42.1%, p=0.01). For overall DDR alteration, the highest frequency was found in hmPCa (63.2%). CONCLUSIONS Through genomic profiling of PCa across various metastatic sites, we identified an extremely low frequency of AR alterations in pmPCa, high prevalence of DDR pathway deficiency in hmPCa and high PTEN alteration rates in vmPCa. We discovered the genomic diversity among bmPCa, hmPCa and pmPCa. Our findings shed new light on the heterogenous prognosis in visceral metastases and hint potential therapeutic targets in both hmPCa and pmPCa.